Modulating effects of WT1 on interferon-ß-vitamin D association in MS.

OBJECTIVE: To investigate whether those genes involved in the vitamin D pathway modulate the relationship between 25-hydroxyvitamin D (25(OH)D) and IFN-ß, the relationship between IFN-ß and sun in predicting 25(OH)D, and the interaction between IFN-ß and 25(OH)D in modulating relapse risk in patients with MS. METHODS: Prospective cohort study of 169 participants with MS and genotype data followed 2002-2005. Gene-IFN-ß and gene-IFN-ß-sun interactions predicting 25(OH)D evaluated by multilevel mixed-effects linear regression. Gene-IFN-ß interactions with 25(OH)D in modulating in relapse risk assessed using survival analysis. RESULTS: The cohort was 71.6% female and of mean age 47.8. Two-independent intronic genotyped SNPs (rs10767935 and rs5030244) in WT1 significantly modified the IFN-ß-25(OH)D association after adjustment (P(interaction) = 0.001, 0.0002; P(adj) = 0.003, 0.006, respectively). There was a marked difference in the interaction between self-reported sun exposure and IFN-ß in predicting 25(OH)D by level of rs10767935, although this did not reach statistical significance. No SNPs modified the interaction between IFN-ß and 25(OH)D in predicting relapse. CONCLUSIONS: We have demonstrated that two-independent SNPs (rs10767935 and rs5030244) in WT1 modified the IFN-ß-25(OH)D association in patients with MS. Some evidence was shown for a difference in the sun-IFN-ß-25(OH)D association by level of rs10767935. These findings indicate that WT1 variants may play a role in altering the effects of IFN-ß on vitamin D in MS.

EBV & HHV6 reactivation is infrequent and not associated with MS clinical course.

BACKGROUND: Among the environmental factors associated with multiple sclerosis (MS) causation, some of the strongest associations are with Epstein-Barr virus (EBV), and to a lesser extent human herpesvirus 6 (HHV6). Associations with clinical course are less conclusive, however. METHODS: We evaluated serum anti-EBV-EA-R IgG and anti-HHV6 IgM, and EBV and HHV6 viral load (VL) for their associations with relapse, disability, and progression in disability in a prospective cohort of 198 participants with clinically definite MS. RESULTS: Anti-EBV-EA-R IgG was detected in 81.8% of cases at study entry, and titers remained essentially unchanged during the study. Anti-HHV6 IgM was detected in only one participant, and EBV-VL (29%) and HHV6-VL (1.8%) were detected in a minority of samples, and where detected levels were low. Our previously demonstrated association between anti-HHV6 IgG and relapse hazard was not affected by adjustment for parameters of reactivation. We found no evidence that any of the viral markers were associated with disability or progression in disability. In relation to relapse, only EBV-VL was positively associated, although this was strongly influenced by a single individual. CONCLUSION: Using a prospective cohort design, we found no convincing evidence that reactivation parameters of EBV or HHV6 were associated with subsequent MS relapse hazard or progression in disability, confirming previous findings, and indicating that herpesvirus reactivation is not an important driver of relapse or disability in this established MS population.

Prevalence and concurrence of anxiety, depression and fatigue over time in multiple sclerosis.

BACKGROUND: Anxiety, depression and fatigue are commonly reported by persons with multiple sclerosis (PwMS). OBJECTIVES: We estimated the prevalence of each factor in a representative sample of PwMS, and in subgroups defined by age, sex and disease duration, at cohort entry and over time. We further examined whether and how these factors clustered together. METHODS: A population-based longitudinal cohort of 198 PwMS was followed 6-monthly for 2.5 years. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety (cut-point >7) and depression (>7) and the Fatigue Severity Scale (FSS) to measure fatigue (≥5). RESULTS: At cohort entry, prevalence of anxiety was 44.5% (95%CI 37-51%), depression 18.5% (95%CI 12.6-23.4%), and fatigue 53.7% (95%CI 47-61%). Fatigue was more common in males than females (RR 1.29, p=0.01), with attenuation of the effect after adjustment for Expanded Disability Status Scale (adjusted RR 1.18, p=0.13). Prevalence of anxiety (but not depression or fatigue) decreased by 8.1% per year of cohort observation (RR 0.92, 95%CI 0.86-0.98, p=0.009), with the effect more pronounced in women (14.6%, RR 0.85, 95%CI 0.79-0.93, -<0.001) than men (2.6%, RR 1.03, 95%CI 0.90-1.17, p=0.77). There was no apparent seasonal variation in the prevalence of any of the three factors (p>0.05). All three factors occurred contemporaneously at cohort entry in a higher proportion of the cohort than expected by chance (p<0.001). CONCLUSIONS: Anxiety, depression and fatigue are common in PwMS and tend to cluster together. The findings are important for clinical management of PwMS and to the exploration of possible shared causal biological pathways.

Use of low-dose mitozantrone to treat aggressive multiple sclerosis: a single-centre open-label study using patient self-assessment and clinical measures of multiple sclerosis status.

BACKGROUND: There is significant evidence supporting the use of mitozantrone in the treatment of multiple sclerosis (MS) but few data on the subtypes of MS that respond or which measures of disease status are most useful. AIMS: To assess the efficacy of low-dose (5 mg/m2 3 monthly) mitozantrone using patient self-assessment questionnaire (SAQ), expanded disability status score (EDSS), multiple sclerosis functional composite score (MSFC), and the fatigue severity scale (FSS). Then, to compare the responses of a subgroup of relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients to treatment, and to assess which measures of MS disease status are the most useful in a study of this type. METHOD: Thirty-one patients with definite (McDonald criteria) active MS were commenced on mitozantrone 5 mg/m2 every 3 months. EDSS, MSFC and FSS data collected before treatment and after 12 months were analysed. The SAQ was administered after at least 12 months of therapy. RESULTS: RRMS patients showed significantly more response to mitozantrone than SPMS patients in terms of MSFC (P = 0.02) and SAQ (P = 0.01). CONCLUSIONS: Low-dose mitozantrone was well tolerated and useful in active RRMS in the short term; however, mitozantrone did not display any useful activity in SPMS patients over this time interval or at the mitozantrone dose used. Patient perception of treatment is a worthwhile outcome measure and the MSFC is the most useful objective measure of MS status change in this type of study.

How large should a skin trephine be for an end stoma?

BACKGROUND: Although much has been written about techniques for making a good stoma, little has been described regarding how to excise a trephine that will perfectly fit a given end stoma. METHODS: A reproducible technique for making a stomal trephine to a precise fit for each stoma is described. RESULTS: More than 20 stomas have been made with good results. CONCLUSION: The skin trephine should have a diameter approximately two-thirds of the width of the crushed bowel end.